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出境医 / 临床实验 / Nivolumab in Biochemically Recurrent dMMR Prostate Cancer

Nivolumab in Biochemically Recurrent dMMR Prostate Cancer

Study Description
Brief Summary:

MMR-deficient cancers of any histologic type appear to be very sensitive to PD-1 blockade with pembrolizumab, and similar data are also beginning to emerge for nivolumab and other immune checkpoint inhibitors. Among the MMR-deficient cancers, the best antitumor responses are often associated with high microsatellite instability (MSI-H status), higher tumor mutational burden (TMB), and higher predicted neoantigen load. Prevalence estimates of MMR deficiency across solid tumor types range from 1% to 20% depending on the type of malignancy. In prostate cancer, 1-3% of unselected cases harbor MMR deficiency and/or microsatellite instability.

For men who previously received definitive treatment for prostate cancer and subsequently develop detectable prostate specific antigen (PSA) levels, the clinical state is known as biochemically recurrent prostate cancer. The current standard of care treatment for patients with biochemically recurrent prostate cancer is either surveillance or androgen deprivation therapy (ADT). ADT has not been shown to provide a survival benefit in this setting, and the decision to initiate ADT will depend on patient preference and perceived risks of the disease. A non-hormonal therapy such as nivolumab would provide an alternative to ADT in patients with biomarker selected (i.e. dMMR, MSI-H, high TMB, or CDK12-altered) biochemically recurrent prostate cancer.


Condition or disease Intervention/treatment Phase
Prostate Cancer Recurrent Prostate Cancer Drug: Nivolumab Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Nivolumab as a Non-Castrating Therapy for MMR-deficient and CDK12- Altered Prostate Cancer With PSA Recurrence After Local Therapy
Actual Study Start Date : January 13, 2020
Estimated Primary Completion Date : January 2025
Estimated Study Completion Date : January 2025
Arms and Interventions
Arm Intervention/treatment
Experimental: Nivolumab in biochemically recurrent prostate cancer
Participants with previous prostatectomy or radiation therapy who subsequently developed detectable prostate specific antigen (PSA) levels ("biochemically recurrent prostate cancer").
 Drug: Nivolumab
Nivolumab 480mg intravenously every 4 weeks
Other Name: Opdivo
Outcome Measures
Primary Outcome Measures :
  1. Percentage of participants with PSA50 response [ Time Frame: up to 6 months post-intervention ]
    Percentage of participants who have received at least 1 dose of Nivolumab who experience a confirmed >=50% decline in prostate specific antigen (PSA) from baseline, as defined by Prostate Cancer Working Group 3 (PCWG3) criteria.


Secondary Outcome Measures :
  1. PSA progression-free survival (PSA-PFS) [ Time Frame: up to 6 months post-intervention ]
    Median time from initiation of therapy until confirmed PSA increase of 25% (PCWG3). Estimated using Kaplan-Meier method.

  2. Number of participants who achieve undetectable PSA [ Time Frame: up to 6 months post-intervention ]
    Number of participants who achieve PSA < 0.1 ng/mL lasting at least 12 weeks.

  3. Metastasis-free survival [ Time Frame: up to 6 months post-intervention ]
    Median time from first dose of nivolumab until the development of radiographic metastatic disease on CT imaging and/or bone scan, as defined by PCWG3

  4. Time to initiation of next systemic therapy [ Time Frame: up to 6 months post-intervention ]
    Median time from first dose of nivolumab until next systemic therapy

  5. Safety and tolerability of Nivolumab in biochemically recurrent prostate cancer as assessed by Incidence of Treatment-Emergent Adverse Events [ Time Frame: up to 100 days post-intervention ]
    Number of participants experiencing adverse events Grade 3 or higher as defined by CTCAE v5.0


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Willing and able to provide signed informed consent and HIPAA authorization for the release of personal health information
  • Males aged 18 years and above
  • Prior local therapy with prostatectomy or EBRT/brachytherapy is required
  • Prior salvage or adjuvant radiation therapy is allowed but not mandated. Radiation therapy must have been completed for at least 6 months.
  • Absolute PSA >=1.0 ng/mL at screening

  • Must have at least one of the following genetic alterations identified using archival tissue (i.e. prostate needle biopsy prior to radiation therapy or prostatectomy specimen):

    • Microsatellite instability (MSI-high) status by clinical grade testing
    • MMR protein loss (MSH2, MSH6, MLH1, PMS2) by immunohistochemistry
    • Inactivating mutation of MSH2, MSH6, MLH1 or PSM2 by clinical grade genomic testing
    • Tumor mutational burden >= 20 mutations/megabase (TMB >=20 muts/Mb) by clinical grade testing
    • Inactivating mutation (at least monoallelic of CDK12 by clinical grade testing
  • Serum testosterone >= 150 ng/dL
  • No radiographic evidence of metastatic disease by CT scan and bone scan, performed within the prior 4 weeks.
  • Karnofsky Performance Status (KPS) >= 70% within 14 days before start of study treatment (ECOG <=1)

  • Participants must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:

    • Hemoglobin >= 9.0 g/dL with no blood transfusion in the past 28 days
    • Absolute neutrophil count (ANC) >= 1.0x10^9 / L
    • Platelet count >= 100 x 10^9 /L
    • Total bilirubin within institutional upper limit of normal (ULN) (in patients with Gilbert's syndrome, total bilirubin <1.5x institutional ULN will be acceptable)
    • Aspartate aminotransferase (AST), Serum Glutamic Oxaloacetic Transaminase (SGOT) / Alanine aminotransferase (ALT), Serum Glutamic Pyruvate Transaminase (SGPT) within institutional ULN
    • Participants must have creatinine clearance estimated using the Cockcroft-Gault equation of >=40 mL/min:

Estimated creatinine clearance = [(140 - age (years)) x weight (kg)] / [serum creatinine (mg/dL) x 72]

  • Participants must have a life expectancy of >= 6 months
  • Male participants and their partners who are sexually active and of childbearing potential must agree to the use of two highly effective forms of contraception in combination, throughout the period of taking study treatment and for 7 months after the last dose of nivolumab to prevent pregnancy in a partner.
  • No evidence (within 5 years) of prior malignancies (except successfully treated basal cell or squamous cell carcinoma of the skin)

Exclusion Criteria:

  • Metastatic disease or currently active second malignancy
  • Prior androgen deprivation therapy (ADT) in the past 6 months. Prior ADT in context of neoadjuvant/adjuvant primary; prior ADT for biochemical recurrence is allowed, as long as no ADT has been administered in past 6 months and testosterone has recovered (>150 ng/dL)
  • Prior oral anti-androgen (e.g. bicalutamide, nilutamide, enzalutamide, apalutamide), or androgen synthesis inhibitor (e.g. abiraterone, orteronel) within the past 2 weeks is not permitted. 5-alpha reductase inhibitor therapy (e.g. finasteride, dutasteride) is allowed, as long as subject has been stable on medication for past 6 months.
  • Involvement in the planning and/or conduct of the study (applies to both BMS staff and/or staff at the study site)
  • Participation in another clinical study with an investigational product during the last 4 weeks/28 days
  • Patients should be excluded if they have had prior systemic treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways
  • Patients should be excluded if they have an active, known or suspected autoimmune disease (e.g. inflammatory bowel disease, rheumatoid arthritis, autoimmune hepatitis, lupus, celiac disease). Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recure in the absence of an external trigger.
  • Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone daily equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses >10mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
  • Permitted therapies include topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g. contrast dye allergy) or for treatment of nonautoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
  • As there is potential for hepatic toxicity with nivolumab, drugs with a predisposition to hepatotoxicity should be used with caution in patients treated with nivolumab-containing regimen.
  • Patients should be excluded if they have a positive test for hepatitis B virus surface antigen (HBVsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
  • Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
  • History of allergy to study drug components
  • History of severe hypersensitivity reaction to any monoclonal antibody

  • Any other serious illness or medical condition that would, in the opinion of the investigator, make this protocol unreasonably hazardous, including but not limited to:

    • Any uncontrolled major infection
    • Cardiac failure NYHA (New York Heart Association) III or IV
    • Crohn's disease or ulcerative colitis
    • Bone marrow dysplasia
    • Known allergy to any of the compounds under investigation
    • Unmanageable fecal incontinence
  • Poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 6 months) myocardial infarction, uncontrolled major seizure disorder, extensive interstitial bilateral lung disease, or any psychiatric disorder that prohibits obtaining informed consent.
Contacts and Locations

Contacts
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Contact: Rana Sullivan, RN 410-614-6337 tomalra@jhmi.edu

Locations
Layout table for location information
United States, Maryland
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Rana Sullivan, RN    410-614-6337    tomalra@jhmi.edu   
Principal Investigator: Mark Markowski, MD/PhD         
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Bristol-Myers Squibb
Investigators
Layout table for investigator information
Principal Investigator: Mark Markowski, MD/PhD Johns Hopkins University
Tracking Information
First Submitted Date  ICMJE July 11, 2019
First Posted Date  ICMJE July 15, 2019
Last Update Posted Date April 12, 2021
Actual Study Start Date  ICMJE January 13, 2020
Estimated Primary Completion Date January 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 11, 2019) 		Percentage of participants with PSA50 response [ Time Frame: up to 6 months post-intervention ]
Percentage of participants who have received at least 1 dose of Nivolumab who experience a confirmed >=50% decline in prostate specific antigen (PSA) from baseline, as defined by Prostate Cancer Working Group 3 (PCWG3) criteria.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 13, 2019)
  • PSA progression-free survival (PSA-PFS) [ Time Frame: up to 6 months post-intervention ]
    Median time from initiation of therapy until confirmed PSA increase of 25% (PCWG3). Estimated using Kaplan-Meier method.
  • Number of participants who achieve undetectable PSA [ Time Frame: up to 6 months post-intervention ]
    Number of participants who achieve PSA < 0.1 ng/mL lasting at least 12 weeks.
  • Metastasis-free survival [ Time Frame: up to 6 months post-intervention ]
    Median time from first dose of nivolumab until the development of radiographic metastatic disease on CT imaging and/or bone scan, as defined by PCWG3
  • Time to initiation of next systemic therapy [ Time Frame: up to 6 months post-intervention ]
    Median time from first dose of nivolumab until next systemic therapy
  • Safety and tolerability of Nivolumab in biochemically recurrent prostate cancer as assessed by Incidence of Treatment-Emergent Adverse Events [ Time Frame: up to 100 days post-intervention ]
    Number of participants experiencing adverse events Grade 3 or higher as defined by CTCAE v5.0
Original Secondary Outcome Measures  ICMJE
 (submitted: July 11, 2019)
  • PSA progression-free survival (PSA-PFS) [ Time Frame: up to 6 months post-intervention ]
    Median time from initiation of therapy until confirmed PSA increase of 25% (PCWG3). Estimated using Kaplan-Meier method.
  • Number of participants who achieve undetectable PSA [ Time Frame: up to 6 months post-intervention ]
    Number of participants who achieve PSA < 0.1 ng/mL lasting at least 12 weeks.
  • Metastasis-free survival [ Time Frame: up to 6 months post-intervention ]
    Median time from first dose of nivolumab until the development of radiographic metastatic disease on CT imaging and/or bone scan, as defined by PCWG3
  • Time to initiation of next systemic therapy [ Time Frame: up to 6 months post-intervention ]
    Median time from first dose of nivolumab until next systemic therapy
  • Safety and tolerability of Nivolumab in biochemically recurrent prostate cancer [ Time Frame: up to 100 days post-intervention ]
    Number of participants experiencing adverse events Grade 3 or higher as defined by CTCAE v5.0
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Nivolumab in Biochemically Recurrent dMMR Prostate Cancer
Official Title  ICMJE Nivolumab as a Non-Castrating Therapy for MMR-deficient and CDK12- Altered Prostate Cancer With PSA Recurrence After Local Therapy
Brief Summary

MMR-deficient cancers of any histologic type appear to be very sensitive to PD-1 blockade with pembrolizumab, and similar data are also beginning to emerge for nivolumab and other immune checkpoint inhibitors. Among the MMR-deficient cancers, the best antitumor responses are often associated with high microsatellite instability (MSI-H status), higher tumor mutational burden (TMB), and higher predicted neoantigen load. Prevalence estimates of MMR deficiency across solid tumor types range from 1% to 20% depending on the type of malignancy. In prostate cancer, 1-3% of unselected cases harbor MMR deficiency and/or microsatellite instability.

For men who previously received definitive treatment for prostate cancer and subsequently develop detectable prostate specific antigen (PSA) levels, the clinical state is known as biochemically recurrent prostate cancer. The current standard of care treatment for patients with biochemically recurrent prostate cancer is either surveillance or androgen deprivation therapy (ADT). ADT has not been shown to provide a survival benefit in this setting, and the decision to initiate ADT will depend on patient preference and perceived risks of the disease. A non-hormonal therapy such as nivolumab would provide an alternative to ADT in patients with biomarker selected (i.e. dMMR, MSI-H, high TMB, or CDK12-altered) biochemically recurrent prostate cancer.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Prostate Cancer
  • Recurrent Prostate Cancer
Intervention  ICMJE Drug: Nivolumab
Nivolumab 480mg intravenously every 4 weeks
Other Name: Opdivo
Study Arms  ICMJE Experimental: Nivolumab in biochemically recurrent prostate cancer
Participants with previous prostatectomy or radiation therapy who subsequently developed detectable prostate specific antigen (PSA) levels ("biochemically recurrent prostate cancer").
Intervention: Drug: Nivolumab
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  • Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000 Feb 2;92(3):205-16.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 11, 2019) 		15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2025
Estimated Primary Completion Date January 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Willing and able to provide signed informed consent and HIPAA authorization for the release of personal health information
  • Males aged 18 years and above
  • Prior local therapy with prostatectomy or EBRT/brachytherapy is required
  • Prior salvage or adjuvant radiation therapy is allowed but not mandated. Radiation therapy must have been completed for at least 6 months.
  • Absolute PSA >=1.0 ng/mL at screening

  • Must have at least one of the following genetic alterations identified using archival tissue (i.e. prostate needle biopsy prior to radiation therapy or prostatectomy specimen):

    • Microsatellite instability (MSI-high) status by clinical grade testing
    • MMR protein loss (MSH2, MSH6, MLH1, PMS2) by immunohistochemistry
    • Inactivating mutation of MSH2, MSH6, MLH1 or PSM2 by clinical grade genomic testing
    • Tumor mutational burden >= 20 mutations/megabase (TMB >=20 muts/Mb) by clinical grade testing
    • Inactivating mutation (at least monoallelic of CDK12 by clinical grade testing
  • Serum testosterone >= 150 ng/dL
  • No radiographic evidence of metastatic disease by CT scan and bone scan, performed within the prior 4 weeks.
  • Karnofsky Performance Status (KPS) >= 70% within 14 days before start of study treatment (ECOG <=1)

  • Participants must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:

    • Hemoglobin >= 9.0 g/dL with no blood transfusion in the past 28 days
    • Absolute neutrophil count (ANC) >= 1.0x10^9 / L
    • Platelet count >= 100 x 10^9 /L
    • Total bilirubin within institutional upper limit of normal (ULN) (in patients with Gilbert's syndrome, total bilirubin <1.5x institutional ULN will be acceptable)
    • Aspartate aminotransferase (AST), Serum Glutamic Oxaloacetic Transaminase (SGOT) / Alanine aminotransferase (ALT), Serum Glutamic Pyruvate Transaminase (SGPT) within institutional ULN
    • Participants must have creatinine clearance estimated using the Cockcroft-Gault equation of >=40 mL/min:

Estimated creatinine clearance = [(140 - age (years)) x weight (kg)] / [serum creatinine (mg/dL) x 72]

  • Participants must have a life expectancy of >= 6 months
  • Male participants and their partners who are sexually active and of childbearing potential must agree to the use of two highly effective forms of contraception in combination, throughout the period of taking study treatment and for 7 months after the last dose of nivolumab to prevent pregnancy in a partner.
  • No evidence (within 5 years) of prior malignancies (except successfully treated basal cell or squamous cell carcinoma of the skin)

Exclusion Criteria:

  • Metastatic disease or currently active second malignancy
  • Prior androgen deprivation therapy (ADT) in the past 6 months. Prior ADT in context of neoadjuvant/adjuvant primary; prior ADT for biochemical recurrence is allowed, as long as no ADT has been administered in past 6 months and testosterone has recovered (>150 ng/dL)
  • Prior oral anti-androgen (e.g. bicalutamide, nilutamide, enzalutamide, apalutamide), or androgen synthesis inhibitor (e.g. abiraterone, orteronel) within the past 2 weeks is not permitted. 5-alpha reductase inhibitor therapy (e.g. finasteride, dutasteride) is allowed, as long as subject has been stable on medication for past 6 months.
  • Involvement in the planning and/or conduct of the study (applies to both BMS staff and/or staff at the study site)
  • Participation in another clinical study with an investigational product during the last 4 weeks/28 days
  • Patients should be excluded if they have had prior systemic treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways
  • Patients should be excluded if they have an active, known or suspected autoimmune disease (e.g. inflammatory bowel disease, rheumatoid arthritis, autoimmune hepatitis, lupus, celiac disease). Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recure in the absence of an external trigger.
  • Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone daily equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses >10mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
  • Permitted therapies include topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g. contrast dye allergy) or for treatment of nonautoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
  • As there is potential for hepatic toxicity with nivolumab, drugs with a predisposition to hepatotoxicity should be used with caution in patients treated with nivolumab-containing regimen.
  • Patients should be excluded if they have a positive test for hepatitis B virus surface antigen (HBVsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
  • Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
  • History of allergy to study drug components
  • History of severe hypersensitivity reaction to any monoclonal antibody

  • Any other serious illness or medical condition that would, in the opinion of the investigator, make this protocol unreasonably hazardous, including but not limited to:

    • Any uncontrolled major infection
    • Cardiac failure NYHA (New York Heart Association) III or IV
    • Crohn's disease or ulcerative colitis
    • Bone marrow dysplasia
    • Known allergy to any of the compounds under investigation
    • Unmanageable fecal incontinence
  • Poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 6 months) myocardial infarction, uncontrolled major seizure disorder, extensive interstitial bilateral lung disease, or any psychiatric disorder that prohibits obtaining informed consent.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Rana Sullivan, RN 410-614-6337 tomalra@jhmi.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04019964
Other Study ID Numbers  ICMJE J1933
IRB00205266 ( Other Identifier: JHM IRB )
CA209-76M ( Other Identifier: Bristol-Myers Squibb )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study Sponsor  ICMJE Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators  ICMJE Bristol-Myers Squibb
Investigators  ICMJE
Principal Investigator: Mark Markowski, MD/PhD Johns Hopkins University
PRS Account Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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